Protein C is a vitamin K dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin.
In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC has anti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis.
Viral hemorrhagic fever is a clinical syndrome associated with significant mortality. Without exception, hemorrhagic fever viruses are enveloped RNA viruses that belong to four viral families: Arenaviridae [Junin, Machupo, Lassa fever], Bunyaviridae [Crimean-Congo hemorrhagic fever, Rift Valley fever, Hantaan and related viruses], Filoviridae [Ebola, Marburg] and Flaviviridae [Dengue, Yellow fever, Omsk hemorrhagic fever, Kyasanur Forest disease], [Cosgriff, T. M., Reviews of Infectious Diseases 11(4): S672-S688, 1989]. These agents produce a wide spectrum of disease severity, but the most extreme manifestations include circulatory instability, increased vascular permeability, and diffuse hemorrhage [Lacy, et al. Advances in Pediatric Infectious Diseases, 12:21-53, 1997].
The underlying mechanism of the bleeding in the hemorrhagic fevers is complex. Possible factors include thrombocytopenia alone, or thrombocytopenia associated with disseminated intravascular coagulation (DIC). Central to the mechanism may well be endothelial cell dysfunction, which has profound implications for both platelets and coagulation. Another possible factor is a decrease in levels of coagulation factors in plasma as the result of either increased consumption or impaired synthesis. Increased consumption occurs in DIC, while impaired synthesis is the likely consequence of liver injury. Liver involvement is a universal occurrence in viral hemorrhagic fever. For example, in Yellow fever, Rift Valley fever and Crimean-Congo hemorrhagic fever, the temporal association of hemorrhage with sever hepatic dysfunction is evident.
Viruses alter hemostasis in two general ways. The first is through direct effect on cellular functions, and the second is through activation of immune and inflammatory pathways. Both mechanisms may lead to variable degrees of cellular injury, including cell death. Activation of coagulation pathways is an important part of immune and inflammatory reactions and accounts for the fibrin deposition that sometimes is observed in these reactions.
Thrombocytopenia is a universal occurrence in viral hemorrhagic fevers. For example, in dengue hemorrhagic fever both changes suggestive of decreased thrombopoiesis and of increased platelet consumption has been determined. This is also the case in hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan and related viruses. Other mechanisms for increased platelet destruction in viral infections include direct interaction of platelets with viruses, DIC, and endothelial injury.
In Ebola and Marburg hemorrhagic fevers, generalized hemorrhages are found in most organs. Focal necrosis without significant inflammation is also widely seen, especially in the lungs, liver, kidneys, and lymphoid organs. DIC is common.
Currently, there is no effective therapy to treat viral hemorrhagic fever. In the absence of viral-specific chemotherapy, management is primarily supportive. Therefore, a need exists for a safe, effective therapy of patients with viral hemorrhagic fever.
The present invention is the first to describe the treatment of viral hemorrhagic fever with protein C. Protein C, with its anticoagulant, anti-inflammatory, and profibrinolytic activities, is useful for the treatment of the hypercoagulable state or protein C deficiency that occurs in viral hemorrhagic fever patients.